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Am J Perinatol
DOI: 10.1055/a-2815-9871
Original Article

Sedation–Analgesia Management in Neonates with Hypoxic–Ischemic Encephalopathy under Therapeutic Hypothermia: Feedback from a Local Study on 51 Patients

Authors

  • Clement Basse 

    1   Pediatric Emergency Department, Lille University Hospital, Lille, France

  • Mohamed Riadh Boukhris 

    2   Department of Neonatology, Lille University Hospital, Lille, France
    3   Research Unit 2694—METRICS, Health Technology Assessment and Medical Practices, University of Lille, Lille, France

  • Laurence Chaton 

    4   National Institute of Health and Medical Research, Unit 1172, University of Lille, Lille, France
    5   Department of Clinical Neurophysiology, Lille University Hospital, Lille, France

  • Laurent Storme 

    2   Department of Neonatology, Lille University Hospital, Lille, France
    3   Research Unit 2694—METRICS, Health Technology Assessment and Medical Practices, University of Lille, Lille, France

  • Emilie Bourel-Ponchel 

    6   National Institute of Health and Medical Research, Joint Research Unit 1105, Research Group on Multimodal Analysis of Brain Fonction, University of Picardie Jules Verne, Amiens, France
    7   Pediatric Neurophysiology Unit, Amiens-Picardie University Hospital, Amiens, France

  • Florence Flamein 

    2   Department of Neonatology, Lille University Hospital, Lille, France
    8   National Institute of Health and Medical Research, Clinical Investigation Center 1403, Lille University Hospital, Lille, France
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Abstract

Objective

The objective of this study is to explore real-world practices in managing sedation–analgesia in a population of neonates with hypoxic–ischemic encephalopathy undergoing therapeutic hypothermia.

Study Design

Retrospective data from neonates admitted with hypoxic–ischemic encephalopathy to the neonatal intensive care unit of Lille University Hospital were collected, between December 31, 2018, and July 15, 2022. Drug and dosage of sedation–analgesia during the 96 hours following therapeutic hypothermia initiation were collected. Neonates were divided into four subgroups for principal component analysis, according to neurological examination at discharge: death, severe sequelae, moderate sequelae, no sequelae.

Results

Neonates with a favorable outcome were exposed to higher cumulative doses. They were more likely to be exposed to polypharmacy, midazolam, and dexmedetomidine, and increasing doses of these. Daily doses of opioids did not vary significantly. Newborns with acute renal failure had lower cumulative doses. There was no significant difference between newborns with and without hepatic cytolysis.

Conclusion

Practice assessments highlight heterogeneity regarding sedation–analgesia, especially within patient groups. Findings indicate that sedation–analgesia is not reassessed as often as it should be to account for specific pharmacokinetic parameters and the physiologic course of recovery.

Key Points

  • Although sedation–analgesia is considered standard of care during therapeutic hypothermia, its use may be iatrogenic; therefore, we evaluated our practices to move toward optimized, personalized management.

  • Neonates with a favorable outcome were more likely to have been exposed to a higher cumulative dose; increasing doses; polypharmacy; midazolam; and dexmedetomidine.

  • Findings indicate that sedation–analgesia is not reassessed as often as it should be.

Keywords

analgesia - hypoxic–ischemic encephalopathy - neonate - sedation - therapeutic hypothermia

Contributors' Statement

C.B., L.C., E.B.-P., and F.F conceived the study. C.B. performed data collection and analysis and drafted the manuscript. E.B.-P. contributed to statistical analysis. L.C., L.S., E.B.-P., M.R.B., and F.F. revised the manuscript critically for important intellectual content. All authors approved the final version.


Data Availability Statement

Deidentified data supporting the findings of this study are available from the corresponding author upon reasonable request.


Supplementary Material



Publication History

Received: 03 October 2025

Accepted: 17 February 2026

Article published online:
02 March 2026

© 2026. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Vega-Del-Val C, Arnaez J, Caserío S. et al; IC-HIE Study Group. Temporal trends in the severity and mortality of neonatal hypoxic-ischemic encephalopathy in the era of hypothermia. Neonatology 2021; 118 (06) 685-692
    Search in Google Scholar
  • 2 Shipley L, Gale C, Sharkey D. Trends in the incidence and management of hypoxic-ischaemic encephalopathy in the therapeutic hypothermia era: a national population study. Arch Dis Child Fetal Neonatal Ed 2021; 106 (05) 529-534
    Search in Google Scholar
  • 3 Meau-Petit V, Tasseau A, Lebail F. et al. Hypothermie contrôlée du nouveau-né à terme après asphyxie périnatale. Arch Pediatr 2010; 17 (03) 282-289
    Search in Google Scholar
  • 4 Thoresen M, Satas S, Løberg EM. et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res 2001; 50 (03) 405-411
    Search in Google Scholar
  • 5 McPherson C, Frymoyer A, Ortinau CM, Miller SP, Groenendaal F. Newborn Brain Society Guidelines and Publications Committee. Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia. Semin Fetal Neonatal Med 2021; 26 (04) 101264
    Search in Google Scholar
  • 6 Joshi M, Muneer J, Mbuagbaw L, Goswami I. Analgesia and sedation strategies in neonates undergoing whole-body therapeutic hypothermia: a scoping review. PLoS One 2023; 18 (12) e0291170
    Search in Google Scholar
  • 7 McPherson C, Miller SP, El-Dib M, Massaro AN, Inder TE. The influence of pain, agitation, and their management on the immature brain. Pediatr Res 2020; 88 (02) 168-175
    Search in Google Scholar
  • 8 Donato J, Rao K, Lewis T. Pharmacology of common analgesic and sedative drugs used in the neonatal intensive care unit. Clin Perinatol 2019; 46 (04) 673-692
    Search in Google Scholar
  • 9 O'Mara K, Weiss MD. Dexmedetomidine for sedation of neonates with hie undergoing therapeutic hypothermia: a single-center experience. AJP Rep 2018; 8 (03) e168-e173
    Search in Google Scholar
  • 10 McAdams RM, McPherson RJ, Kapur R, Phillips B, Shen DD, Juul SE. Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats. Pediatr Res 2015; 77 (06) 772-778
    Search in Google Scholar
  • 11 Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 2016; 17 (11) 705-717
    Search in Google Scholar
  • 12 Jevtovic-Todorovic V, Hartman RE, Izumi Y. et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23 (03) 876-882
    Search in Google Scholar
  • 13 Zwicker JG, Miller SP, Grunau RE. et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine. J Pediatr 2016; 172: 81-87.e2
    Search in Google Scholar
  • 14 Duerden EG, Guo T, Dodbiba L. et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol 2016; 79 (04) 548-559
    Search in Google Scholar
  • 15 McPherson C, Haslam M, Pineda R, Rogers C, Neil JJ, Inder TE. Brain injury and development in preterm infants exposed to fentanyl. Ann Pharmacother 2015; 49 (12) 1291-1297
    Search in Google Scholar
  • 16 Nuzum TA, Kazmi SH, Wachtel EV. The effect of using dexmedetomidine versus morphine as sedation on long-term neurodevelopmental outcomes of encephalopathic neonates undergoing therapeutic hypothermia. J Perinatol 2025; 45 (08) 1081-1086
    Search in Google Scholar
  • 17 Simbruner G, Mittal RA, Rohlmann F, Muche R. neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics 2010; 126 (04) e771-e778
    Search in Google Scholar
  • 18 Lally PJ, Pauliah S, Montaldo P. et al. Magnetic resonance biomarkers in neonatal encephalopathy (MARBLE): a prospective multicountry study. BMJ Open 2015; 5 (09) e008912
    Search in Google Scholar
  • 19 Azzopardi DV, Strohm B, Edwards AD. et al; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361 (14) 1349-1358
    Search in Google Scholar
  • 20 Favié LMA, Groenendaal F, van den Broek MPH. et al; PharmaCool study group. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS One 2019; 14 (02) e0211910
    Search in Google Scholar
  • 21 Frymoyer A, Bonifacio SL, Drover DR, Su F, Wustoff CJ, Van Meurs KP. Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia. J Clin Pharmacol 2017; 57 (01) 64-76
    Search in Google Scholar
  • 22 Favié LMA, de Haan TR, Bijleveld YA. et al. Prediction of drug exposure in critically ill encephalopathic neonates treated with therapeutic hypothermia based on a pooled population pharmacokinetic analysis of seven drugs and five metabolites. Clin Pharmacol Ther 2020; 108 (05) 1098-1106
    Search in Google Scholar
  • 23 Statistical Analysis Software. SAS/STAT. Accessed July 21, 2023 at: https://www.sas.com/fr_fr/software/stat.html
  • 24 Lê S, Josse J, Husson F. FactoMineR : an r package for multivariate analysis. J Stat Softw 2008;25
  • 25 Vittner D, Butler S, Lawhon G, Buehler D. The newborn individualised developmental care and assessment program: a model of care for infants and families in hospital settings. Acta Paediatr 2025; 114 (04) 743-751
    Search in Google Scholar
  • 26 El-Dib M, Munster C, Szakmar E, Inder T, Gunn AJ. Late onset oxygen requirement following neonatal therapeutic hypothermia. Acta Paediatr 2020; 109 (11) 2258-2265
    Search in Google Scholar
  • 27 El-Dib M, Szakmar E, Chakkarapani E, Aly H. Newborn Brain Society Guidelines and Publications Committee. Challenges in respiratory management during therapeutic hypothermia for neonatal encephalopathy. Semin Fetal Neonatal Med 2021; 26 (04) 101263
    Search in Google Scholar
  • 28 Effects of therapeutic hypothermia on medications. John Wiley and Sons Ltd; 2014: 44-47
    Search in Google Scholar
  • 29 Morris EE, Howell MJ, Pickup E, Iber C, Wang SG. Pediatric sleep and pain: etiologies, consequences, and clinical considerations. J Clin Sleep Med 2022; 18 (09) 2281-2289
    Search in Google Scholar